Questions: Myocardial Contractility and Contraction Mechanics

Question 1

During a cardiac action potential, L-type calcium channels on the T-tubule open and allow a small influx of extracellular calcium. What is the immediate consequence of this trigger calcium?

• A. Trigger calcium directly binds troponin C and initiates cross-bridge cycling without involving the sarcoplasmic reticulum
• B. Trigger calcium binds ryanodine receptors (RyR2) on the SR, causing them to release a much larger store of calcium into the cytoplasm
• C. Trigger calcium activates beta-1 adrenergic receptors, initiating the sympathetic signaling cascade
• D. Trigger calcium phosphorylates phospholamban, activating SERCA to pump more calcium into the SR

Answer: (B)

This is the calcium-induced calcium release (CICR) mechanism that distinguishes cardiac from skeletal muscle. The small L-type channel influx is a trigger, not the primary activator — it opens SR ryanodine receptors that then flood the cytoplasm with much more calcium. This two-step amplification is what gives the heart precise gain control over contraction strength. Options C and D describe downstream sympathetic signaling events, not the immediate consequence of the trigger influx.

Question 2

A patient experiences significant blood loss, reducing venous return to the heart. According to the Frank-Starling mechanism, what happens to stroke volume, and why?

• A. Stroke volume increases to compensate for blood loss — the heart pumps harder when it receives less blood
• B. Stroke volume decreases because less ventricular filling means less sarcomere stretch, reduced calcium sensitivity, and weaker contraction
• C. Stroke volume is unchanged because the Frank-Starling mechanism only responds to sympathetic stimulation, not filling changes
• D. Stroke volume increases briefly then decreases as sympathetic drive kicks in

Answer: (B)

The Frank-Starling mechanism is intrinsic and passive: sarcomere length determines contraction force. With less blood entering the ventricle (reduced preload), sarcomeres are less stretched, calcium sensitivity is lower, and filament overlap is suboptimal — so contraction is weaker and stroke volume falls. This is the mechanism that normally matches cardiac output to venous return. Option C confuses the Frank-Starling mechanism with sympathetic modulation; they are two separate, complementary systems.

Question 3

The Frank-Starling mechanism increases cardiac force primarily by causing more calcium to be released from the sarcoplasmic reticulum when the ventricle is more filled.

• T. True
• F. False

Answer: False

The Frank-Starling mechanism does not primarily act by increasing SR calcium release. It works through two intrinsic mechanical effects of sarcomere stretch: (1) improved overlap of thick and thin filaments in the physiological range of sarcomere lengths, and (2) increased calcium sensitivity of the contractile proteins (particularly troponin C) when the myofilaments are stretched. More calcium release from the SR is how sympathetic stimulation increases contractility — a distinct mechanism.

Question 4

Beta-1 adrenergic stimulation increases cardiac contractility in part by phosphorylating phospholamban, which removes its inhibition of the SERCA pump and allows more calcium to be loaded into the SR for the next beat.

• T. True
• F. False

Answer: True

This is a key step in the sympathetic contractility pathway. Normally, phospholamban inhibits SERCA2a (the SR calcium ATPase), limiting SR calcium loading. PKA phosphorylation of phospholamban releases this inhibition, allowing SERCA to pump calcium into the SR more rapidly between beats. This loads more calcium for the next action potential's CICR, increasing the amplitude of the cytoplasmic calcium transient. It also accelerates relaxation (lusitropy), which is essential for allowing adequate filling at high heart rates.

Question 5

Explain how the Frank-Starling mechanism and sympathetic stimulation each increase cardiac output, and how they work together during vigorous exercise.

Model answer: The Frank-Starling mechanism is intrinsic: when venous return increases, more blood fills the ventricle during diastole, stretching sarcomeres. This stretch increases calcium sensitivity and optimizes filament overlap, producing a stronger contraction without any neural input. Sympathetic stimulation is extrinsic: norepinephrine activates beta-1 receptors, triggering PKA phosphorylation of L-type channels (more trigger calcium), phospholamban (more SR loading), and troponin I (faster relaxation). During exercise, both operate simultaneously: skeletal muscle pump and increased heart rate drive more blood to the heart (Starling effect), while sympathetic drive shifts the Starling curve upward so the heart ejects more forcefully at any given filling level.

The two mechanisms are complementary: Starling handles beat-to-beat matching of output to input; sympathetic drive shifts the baseline upward for sustained high-demand states. Neither alone can produce the five-fold increase in cardiac output required during maximal exercise.